Parkinson's disease, a progressive neurodegenerative disorder, is characterized by loss of neurons that synthesize and release dopamine. This loss of dopaminergic neurons manifests itself in symptoms such as rigidity, resting tremors (shaking), poverty of movement (akinesia), slowness of movement (bradykinesis), and changes in gait and posture. Treatment of Parkinson's disease generally is based on therapeutic administration of substances that can compensate for the lack of dopaminergic neurotransmission due to the loss of dopamine-secreting neurons. A classic treatment regime includes chronic oral administration of levodopa, which is decarboxylated in the brain to form dopamine. Often, after several years of treatment with levodopa, abnormalities emerge, including involuntary movements during the “on” phase of clinical improvement and re-emergence of Parkinson's-type symptoms during “off” phases.
Apomorphine, an effective agonist at both dopamine receptors in the nervous system, has been used for treatment of Parkinson's disease in patients that have become resistant to or have developed adverse side effects with associated with chronic levodopa therapy. Typically, due to its short duration of effectiveness, apomorphine is administered by repeated subcutaneous injections or continuous parenteral infusion via a pump. These means of administration are inconvenient, in the case of subcutaneous injection, and technically difficult, in the case of pump administration, especially for Parkinson's patients whose dexterity is impaired due to the disease itself and the movements associated with chronic levodopa treatment. Apomorphine may also be administered transdermally (U.S. Pat. No. 5,562,917), intranasally (U.S. Pat. No. 5,756,483), as a topically-applied gel (U.S. Pat. No. 5,939,094), or sublingually (U.S. Pat. No. 5,994,363). None of these methods permits continuous administration over long periods of time.
Dopamine agonists have also been used for treatment of parkinsonism which results from central nervous system injury by toxin exposure or a disease condition such as encephalitis, erectile dysfunction, restless leg syndrome, and hyperprolactinemia.
There is a need for an improved means of administration that would permit continuous dosing of dopamine agonists over an extended period of time of several months or longer, without the adverse side effects associated with peaks and troughs in plasma levels due to discontinuous dosing, or reliance on cumbersome mechanical equipment such as a pump.